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microRNA-7 inhibition protects human osteoblasts from dexamethasone via activation of epidermal growth factor receptor signaling

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Abstract

Sustained dexamethasone (Dex) treatment could induce secondary osteoporosis, osteonecrosis, or even bone fractures. Dex can induce potent cytotoxicity in cultured human osteoblasts. The aim of this study was to test the potential role of microRNA-7 (miR-7), which targets the epidermal growth factor receptor (EGFR), in Dex-treated human osteoblasts. In OB-6, hFOB1.19, and primary human osteoblasts, miR-7 depletion by a lentiviral antagomiR-7 construct (LV-antagomiR-7) increased EGFR expression and downstream Akt activation, protecting cells from Dex-induced viability reduction, cell death, and apoptosis. In contrast, forced overexpression of miR-7 by a lentiviral miR-7 construct (LV-miR-7) inhibited EGFR expression and Akt activation, potentiating Dex-induced cytotoxicity in OB-6, hFOB1.19, and primary human osteoblasts. EGFR is the primary target of miR-7 in human osteoblasts. Luciferase activity of the EGFR 3-untranslated region was enhanced by LV-antagomiR-7, but decreased by LV-miR-7 in OB-6 cells. Further, LV-antagomiR-7-induced osteoblast cytoprotection against Dex was abolished by the EGFR inhibitors AG1478 and PD153035. Moreover, neither LV-antagomiR-7 nor LV-miR-7 was functional in EGFR-KO OB-6 cells. We also show that miR-7 is upregulated in the necrotic femoral head tissues of Dex-administered patients, correlating with EGFR downregulation. Together, we conclude that miR-7 inhibition protects human osteoblasts from Dex via activation of EGFR signaling.

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Acknowledgements

This work was generously supported by grants from the National Natural Science Foundation of China (81501866), Jiangsu Provincial Young Medical Talent Foundation (QNRC2016411), Jiangsu Six One Project (LGY2018035), Jiangsu 333 Talent Peak Program (To J. F.), and Nantong 226 High-level Talents Project (To J. F.).

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  1. Jian-bo Fan and Wei Liu have contributed equally to this work.

Authors and Affiliations

  1. Department of Orthopedics, Jinling Hospital, Jinling Clinical Medical College of Nanjing Medical University, Nanjing, 210002, Jiangsu, People’s Republic of China

    Jian-bo Fan & Jian-ning Zhao

  2. Department of Orthopedics, Affiliated Hospital 2 of Nantong University, Nantong, 226001, Jiangsu, People’s Republic of China

    Jian-bo Fan, Wei Liu, Xin-hui Zhu, Sheng-yu Cui & Zhi-ming Cui

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  1. Jian-bo Fan
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  2. Wei Liu
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Correspondence to Jian-ning Zhao.

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Fan, Jb., Liu, W., Zhu, Xh. et al. microRNA-7 inhibition protects human osteoblasts from dexamethasone via activation of epidermal growth factor receptor signaling. Mol Cell Biochem 460, 113–121 (2019). https://doi.org/10.1007/s11010-019-03575-y

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  • DOI: https://doi.org/10.1007/s11010-019-03575-y

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